Potent, Rationally Designed Inhibitors of Squalene Synthase

Biller, Scott A.; Sofia, Michael J.; Abt, Jeffrey W.; DeLange, Barbara; Dickson, John K.; Forster, Cornelia; Gordon, Eric M.; Harrity, Thomas; Magnin, David R.; Marretta, Joseph; Rich, Lois C.; Ciosek, Carl P.

doi:10.1021/bk-1992-0497.ch007

Cited by 9 publications

(24 citation statements)

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“…Consistent with the triprenylated compounds, the diprenyl Z olefin 4d showed weaker HMGR suppression than the diprenyl E olefin 4c. Biller et al 35 have observed a similar phenomenon within a series of squalene synthase inhibitors, which suggests that a common recognition element exists for both HMGR and squalene synthase suppression.…”

Section: Resultsmentioning

confidence: 77%

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Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogs of the Tocotrienols

Pearce¹,

Parker²,

Deason³

et al. 1994

J. Med. Chem.

128

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Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.

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Section: Resultsmentioning

confidence: 77%

“…Purification of the crude material by flash chromatography (20:1 hexanes:ether) yielded 34 as a light oil (1.0 g, 2.0 mmol, 57% overall yield). 5,6,7,8-Tetrahydro-6-methyl-6-(4,8,12-trimethyl-3(E),7-(£),ll-tridecatrienyl)-2-naphthalenol (35). Silyl ether 34 (1.0 g, 2.0 mmol) was dissolved in 5 mL of ether.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogs of the Tocotrienols

Pearce¹,

Parker²,

Deason³

et al. 1994

J. Med. Chem.

128

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“…The optimal linear alkyl chain length in this series is the dodecyl ether 6c, which is about >12 (25% at 12 mpk) 3r ch3och2ch2ch2 25.0 (0.65) 0.03 20 3s h2nch2ch2ch2 nac at 161 nM >12 (0% at 12 mpk) 3t hoocch2ch2 nac at 161 nM >12 (-20% at 12 mpk) " L-694,599 was used as a control; its IC50 values are given in parentheses. 6 Relative activity.c Not active. d Not done.…”

Section: Resultsmentioning

confidence: 99%

“…If the compound was found to be significantly active (inhibition greater than 50%), the compound was then titrated to determine the ED6o values. The titrations were done with dosage groups (six mice per group) with serial dilutions that differed by a factor of 2 (typically 24,12,6, and 2 mg/kg). ED50 values were determined from a plot of percent inhibition vs the log dose.…”

Section: Methodsmentioning

confidence: 99%

Structure-Activity Relationships of C1 and C6 Side Chains of Zaragozic Acid A Derivatives

Ponpipom¹,

Girotra²,

Bugianesi³

et al. 1994

J. Med. Chem.

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Systematic modification of the C6 acyl side chain of zaragozic acid A, a potent squalene synthase inhibitor, was undertaken to improve its biological activity. Simplification of the C6 side chain to the octanoyl ester has deleterious effects; increasing the linear chain length improves the in vitro activity up to the tetradecanoyl ester. An omega-phenoxy group is a better activity enhancer than an omega-phenyl group. A number of C6 carbamates, ethers, and carbonates were prepared and found to have similar activity profiles as the C6 esters. In the preparation of C6 ethers, C4 and C4,6 bisethers were also isolated; their relative activity is: C6 > C4 > C4,6. These C6 long-chain derivatives are subnanomolar squalene synthase inhibitors; they are, however, only weakly active in inhibiting hepatic cholesterol synthesis in mice. The C6 short-chain derivatives are much less active in vitro, but they all have improved oral activity in mice. Modification of the C1 alkyl side chain of the n-butanoyl analogue (ED50 4.5 mg/kg) did not improve the po activity further. A number of these C6 long-chain derivatives are also potent antifungal agents in vitro.

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“…For example, while several routes to hydroxybisphosphonates are known [ 15 ], any attempt to incorporate an ether linkage through the corresponding alkoxide after formation of the bisphosphonate would face the strong possibility of phosphonate–phosphate rearrangement [ 15 – 17 ]. However, diethyl hydroxymethylphosphonate ( 7 , Scheme 1 ) is known to react with a base and geranyl bromide to afford the ether 8 in good yield [ 18 ]. With compound 8 in hand, formation of the second C–P bond occurred readily upon treatment with base and diethyl chlorophosphate [ 19 – 23 ] to give the bisphosphonate ether 9 in modest yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

Zhou¹,

Reilly²,

Loerch³

et al. 2014

Beilstein J. Org. Chem.

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SummaryA set of bisphosphonate ethers has been prepared through sequential phosphonylation and alkylation of monophosphonate ethers. After formation of the corresponding phosphonic acid salts, these compounds were tested for their ability to inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS). Five of the new compounds show IC50 values of less than 1 μM against GGDPS with little to no activity against the related enzyme farnesyl diphosphate synthase (FDPS). The most active compound displayed an IC50 value of 82 nM when assayed with GGDPS, and no activity against FDPS even at a 10 μM concentration.

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Potent, Rationally Designed Inhibitors of Squalene Synthase

Cited by 9 publications

References 0 publications

Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogs of the Tocotrienols

Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogs of the Tocotrienols

Structure-Activity Relationships of C1 and C6 Side Chains of Zaragozic Acid A Derivatives

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

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